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Germ-line msh6 Mutations in Colorectal Cancer Families¹

Ludwig Institute for Cancer Research, Department of Medicine and Cancer Center, University of California San Diego Medical School, La Jolla, California 92093 [R. D. K., J. D. T., J. S., M. F. K., R. D. G., J. W.]; Department of Epidemiology, University of California Irvine School of Medicine, Irvine, California 92697 [D. P., A. Z., H. A-C.]; Division of Gastroenterology, Brigham and Women’s Hospital, Boston, Massachusetts 02115 [S. S.]; and Department of Cancer Biology [S. W.], Molecular Diagnostics Laboratory [E. A. F.], and Department of Adult Oncology [J. E. G., S. S., F. P. L.], Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Hereditary nonpolyposis colorectal carcinoma (HNPCC) is due primarily to inherited mutations in two mismatch repair genes, MSH2 and MLH1, whereas germ-line mutations in other mismatch repair genes are rare. We examined the frequency of germ-line msh6 mutations in a population-based series of 140 colorectal cancer patients, including 45 sporadic cases, 91 familial non-HNPCC cases, and 4 HNPCC cases. Among the 91 population-based familial non-HNPCC cases, germ-line msh6 mutations were found in 6 patients (7.1% of probands analyzed; median age at diagnosis, 61 years). These mutations included a splice site mutation, a frameshift mutation, two missense mutations that were demonstrated to be loss of function mutations, and two missense mutations for which functional studies were not possible. In contrast, germ-line msh6 mutations were not found in any of the 45 sporadic cases and the 4 HNPCC cases in the population-based series or in the second series of 58 clinic-based, primarily HNPCC families. Our data suggest that germ-line msh6 mutations predispose individuals to primarily late-onset, familial colorectal carcinomas that do not fulfill classic criteria for HNPCC.

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